This use of “chirality-assisted synthesis” is a fundamentally new approach to control the shape of large molecules — one of the foundational needs for making a new generation of complex synthetic materials, including polymers and medicines.

Like NanoLegos

Experimenting with anthracene, a substance found in coal, Schneebeli and his team assembled C-shaped strips of molecules that, because of their chirality, are able to join each other in only one direction. “They’re like Legos,” Schneebeli explains. These molecular strips form a rigid structure that’s able to hold rings of other chemicals “in a manner similar to how a five-sided bolt head fits into a pentagonal wrench,” the team writes.

The C-shaped strips can join to each other, with two bonds, in only one geometric orientation. So, unlike many chemical structures — which have the same general formula but are flexible and can twist and rotate into many different possible shapes — “this has only one shape,” Schneebeli says. “It's like a real wrench,” he says — with an opening a hundred-thousand-times smaller than the width of human hair: 1.7 nanometers.

“It completely keeps its shape,” he explains, even in various solvents and at many different temperatures, “which makes it pre-organized to bind to other molecules in one specific way,” he says.

A blue wrench (of molecules) to adjust a green bolt (a pillarene ring) that binds a yellow chemical “guest.” It’s a new tool — just 1.7 nanometers wide — that could help scientists catalyze and create a host of useful new materials. (Image courtesy of Severin Schneebeli)

This wrench, the new study shows, can reliably bind to a family of well-known large molecules called “pillarene macrocycles.” These rings of pillarene have, themselves, often been used as the “host,” in chemistry-speak, to surround and modify other “guest” chemicals in their middle — and they have many possible applications from controlled drug delivery to organic light-emitting substances.

“By embracing pillarenes,” the UVM team writes, “the C-shaped strips are able to regulate the interactions of pillarene hosts with conventional guests.” In other words, the chemists can use their new wrench to remotely adjust the chemical environment inside the pillarene in the same way a mechanic can turn an exterior bolt to adjust the performance inside an engine.

The new wrench can make binding to the inside of the pillarene rings “about one hundred times stronger,” than it would be without the wrench, Schneebeli says.
Making models

Also, “because this kind of molecule is rigid, we can model it in the computer and project how it looks before we synthesize it in the lab,” says UVM theoretical chemist Jianing Li, Schneebeli’s collaborator on the research and a co-author on the new study. Which is exactly what she did, creating detailed simulations of how the wrench would work, using computer processors in the Vermont Advanced Computing Core.

“This is a revolutionary idea,” Li said, “We have 100 percent control of the shape, which gives great atomic economy — and lets us know what will happen before we start synthesizing in the lab.”

In the lab, post-doctoral researcher and lead author Xiaoxi Liu, undergraduate Zackariah Weinert ’16, and other team members were guided by the computer simulations to test the actual chemistry. Using a mass spectrometer and an NMR spectrometer in the UVM chemistry department, the team was able to confirm Schneebeli’s idea.

Creative simplicity

Sir Fraser Stoddart, a world-leading chemist at Northwestern University, described the new study as, “Brilliant and elegant! Creative and simple.” And, indeed, it’s the simplicity of the approach that makes it powerful, Schneebeli says. “It’s all based on geometry that controls the symmetry of the molecules. This is the only shape it can take — which makes it very useful.”

Next, the team aims to modify the C-shaped pieces — which are tied together with two bonds formed between two nitrogens and bromines — to create other shapes. “We’re making a special kind of spiral which is going to be flexible like a real spring,” Schneebeli explains, but will hold its shape even under great stress.

“This helical shape could be super-strong and flexible. It could create new materials, perhaps for safer helmets or materials for space,” Schneebeli says. “In the big picture, this work points us toward synthetic materials with properties that, today, no material has."

Chirality-assisted synthesis (CAS) is a general approach to control the shapes of large molecular strips. CAS is based on enantiomerically pure building blocks that are designed to strictly couple in a single geometric orientation. Fully shape-persistent structures can thus be created, even in the form of linear chains. With CAS, selective recognition between large host and guest molecules can reliably be designed de novo. To demonstrate this concept, three C-shaped strips that can embrace a pillar[5]arene macrocycle were synthesized. The pillar[5]arene bound to the strips was a better host for electron-deficient guests than the free macrocycle. Experimental and computational evidence is provided for these unique cooperative interactions to illustrate how CAS could open the door towards the precise positioning of functional groups for regulated supramolecular recognition and catalysis.

Video of Computer Simulation of nanoscale wrench

Like a wrench hunting for a bolt, a video computer simulation, created by UVM chemist Jianing Li, shows a pillarene ring getting found and embraced by a larger chemical structure. The UVM team made models of both pieces and then, programmed with Newton’s equations, watched how they interacted.